The introduction of hyperkalemia cardioplegia revolutionized cardiac surgery by making the performance of complex operations possible in a quiet, bloodless field. However, myocardial protection with hyperkalemic cardioplegia is far from perfect. Postoperative myocardial dysfunction is commonly encountered, and at times, can be severe and prolonged. The inadequacies of myocardial protection with hyperkalemic cardioplegia are perhaps best documented by the continuing quest over the last 20 years to improve these solutions through innumerable changes in their chemical composition, temperature, and delivery. The basis of hyperkalemic cardioplegia is its ability to depolarize the cell membrane and create electromechanical asystole. Unfortunately, there are ongoing metabolic processes and damaging ion fluxes that occur at depolarized membrane potentials. These have been shown to lead to cell swelling and myocyte calcium overload, both of which play critical roles in cellular ischemic damage and reperfusion injury. The central hypothesis to be tested in this proposal is that a cardioplegic solution which arrests the heart at hyperpolarized potentials, the natural resting state of the cell membrane, would avoid the detrimental aspects of depolarized arrest. Metabolic demand is minimal and transmembrane ionic gradients are balanced by the membrane potential at rest. A new class of agents, ATP sensitive potassium (K ATP) channel openers, will be used to induce hyperpolarized arrest. To test this central hypothesis and its corollaries, a series of experiments are planned with the following specific aims; 1. To determine the basic properties of K ATP channel openers as cardioplegic agents. By examining reperfusion ventricular function in an isolated blood perfused rabbit hart model, careful dose-response curves will be generated for several K ATP channel openers. The length of protection conveyed by a single dose of the drug will be determined by measuring the time to ischemic contracture. Finally, infusion and reinfusion strategies will be examined during prolonged arrest. These initial studies will define the optimal cardioplegic agent for further investigation. 2. To est the hypotheses that the pH, [Ca2+] and [Mg2+] of the delivery solution have a direct effect on the efficacy of hyperpolarized arrest of the K ATP channel openers. These ions have been shown to effect K ATP channels in single cell experiments. These studies will define the optimal delivery solution. 3. To test the hypothesis that hastening electrical asystole will improve myocardial protection with K ATP channel openers. The sodium channel blocker, procaine, will be used as an adjunctive agent in our isolated rabbit heart model. 4. To test the hypothesis that augmenting membrane hyperpolarization with an adjunctive agent will improve myocardial protection and minimize drug toxicity. Adenosine will be used to activate A1 receptors which are coupled to the K ATP channel. 5. To test the hypothesis that hyperpolarized arrest with the optimal K ATP channel opener solution is superior to hyperkalemic depolarized arrest in our isolated rabbit heart model. Multiple physiological (functional, rheological, electrophysiological, metabolic, histological) end-points will be measured to define the mechanisms of myocardial protection. 6. To test the hypothesis that hyperpolarized arrest is superior to depolarized arrest in a more clinically relevant intact porcine cardiopulmonary bypass preparation in both normal and ischemic hearts. it is our belief that hyperpolarized arrest will simplify and extend current techniques of myocardial protection during surgical global ischemia.
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